The understanding of the functions of orphan and other receptors in the CNS through the use of nucleotide probes, specific amino acid sequences, and other methods is the most important purpose of this project. The large number of cloned receptors with unknown function requires an integrated approach to generate clinically relevant knowledge. During the next five years the project will center on (a) sigma receptors and (b) on the novel receptor-protein tyrosine phosphatases. (a) Study I will examine the mechanism of the down-regulation of the sigma binding sites produced by the chronic administration of haloperidol. The nature of this inhibition and the role of haloperidol metabolites will be studied using radioreceptor assays followed by computer-assisted modeling, radioreceptor autoradiography and histopathologic examinations. These studies have important implications for the understanding of neuroleptic-induced tardive dyskinesia and other side effects. (b) Study II will determine the expression of receptor-protein tyrosine phosphatases MRNA levels before, during and after the rapid sprouting of axons and dendrites in the developing rat brain, and will map their distribution in the adult brain. Quantitative Northern analysis, in situ hybridization, and immunohistochemical techniques will be used to determine (i) whether cells producing specifically characterized receptor-protein tyrosine phosphatases are regionally distributed in adult rat brain and (ii) whether they are altered during development and synaptogenesis. The application of molecular biological techniques to the investigation of receptor-protein tyrosine phosphatases in the brain will contribute to our understanding of their physiological role and putative involvement in pathological processes such as Alzheimer and Parkinson's diseases. Mice, rats and guinea pigs will be used for these studies.